DESCRIPTION: (Principal Investigator's Abstract) The fundamental objective of this research program is to develop efficient strategies and methodology for total synthesis of a variety of naturally occurring biologically active marine alkaloids. A primary goal is also to complete some total syntheses which are currently well under way. Included as targets are sarain A, as well as the antitumor madangamines, polycyclic marine alkaloids which are believed to have a common biogenetic origin from a bis-pyridine macrocycle. In addition, work will be initiated on a total synthesis of the anticancer marine alkaloid fasicularin utilizing a novel variant of an intramolecular N-acylimine/olefin (4+2)-cycloaddition, followed by an intramolecular keto carbene insertion into an N-H bond. Furthermore, the radical based methodology for generation of N-acylimines previously funded by this grant will be extended to acyclic systems, and then applied in the fasicularin work. Finally, methodology for regioselective construction of highly substituted pyridines, which are components of the thiostreptone class of antibiotics, will be pursed via an intramolecular hetero Diels-Alder strategy. In all of these projects a strong emphasis has been placed on developing new, practical methods of organic synthesis.